Regulation of signaling pathway, cell cycle, and cell growth in atherosclerosis

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There is an increasing demand to investigate the mechanisms of the formation of atherosclerosis, as diseases due to vascular complications of diabetes, hyperlipidemia and hypertension is rapidly increasing in Japan according to the recent changes in life style. Deregulation of the growth and apoptosis of vascular endotherial cells and smooth muscle cells are believed to play important roles in the formation of atherosclerosis. Therefore, it is important to study the controls of signal transduction and cell cycle of these cells during this process, which may lead to a development of the way of prevention. We have discovered the p27 CDK inhibitor, an apparent brake of the cell cycle, and have shown that CDK inhibitors, including p27, may play important roles in the regulation of cell differentiation and proliferation. Using vascular endotherial cell, we have shown that the two CDK inhibitors, p21Cip1 and p27Kip1, may have different roles in the regulations of apoptosis of the cell by the TNF-a stimuli. In the presence of insulin in the culture medium, TNF-a induced p27, where without insulin, TNF-a decreased p27 and induced p21. Apoptosis was induced more efficiently with the cells untreated with insulin, therefore, it is likely that p27 may have suppressive role, where p21 may induce apoptosis. As apoptosis of the endotherial cells are important in the formation of atherosclerotic changes, CDK inhibitors may be utilized in the prevention. Progression of atherosclerosis may be induced through a vicious cycle composed of a combination of cytokines, chemokines, adhesion molecules and extracellular matrix locally expressed by macrophage, lymphocyte, endotherial cell and smooth muscle cells. Therefore, we will investigate the effect of these molecules on the apoptosis of endotherial cells to seek for the way to prevent atherosclerosis.